Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Nov 27;11(12):1711.
doi: 10.3390/antibiotics11121711.

Next-Generation Polymyxin Class of Antibiotics: A Ray of Hope Illuminating a Dark Road

Abdullah Tarık Aslan  1   2 , Murat Akova  3 , David L Paterson  2   4
Affiliations
Review

Next-Generation Polymyxin Class of Antibiotics: A Ray of Hope Illuminating a Dark Road

Abdullah Tarık Aslan et al. Antibiotics (Basel). .

Abstract

Although new-generation antimicrobials, in particular β-lactam/β-lactamase inhibitors, have largely replaced polymyxins in carbapenem-resistant Gram-negative bacterial infections, polymyxins are still needed for carbapanem-resistant Acinetobacter baumannii infections and in settings where novel agents are not readily available. Despite their potent in vitro activity, the clinical utility of polymyxins is significantly limited by their pharmacokinetic properties and nephrotoxicity risk. There is significant interest, therefore, in developing next-generation polymyxins with activity against colistin-resistant strains and lower toxicity than existing polymyxins. In this review, we aim to present the antibacterial activity mechanisms, in vitro and in vivo efficacy data, and toxicity profiles of new-generation polymyxins, including SPR206, MRX-8, and QPX9003, as well as the general characteristics of old polymyxins. Considering the emergence of colistin-resistant strains particularly in endemic regions, the restoration of the antimicrobial activity of polymyxins via PBT2 is also described in this review.

Keywords: MRX-8; PBT2; QPX9003; SPR206; colistin; polymyxins.

PubMed Disclaimer

Conflict of interest statement

M.A. has received honoraria for educational activities from Pfizer, MSD, Gilead and Genentech, and research support from Pfizer and Gilead. D.L.P. reports research grants from Merck, Pfizer, and Shionogi. D.L.P. has received honoraria for advisory board membership or consultancies from the AMR Action Fund, Merck, Pfizer, Shionogi, GSK, Qpex, Spero, Entasis, VenatoRx, BioMerieux, and Accelerate. All other authors declare that they have no conflicts of interest. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Figures

Figure 1
Figure 1
Chemical structure of polymyxin B and colistin. Amino acid residue differing between polymyxin B and colistin at R6 position: D-Phe for polymyxin B and D-Leu for colistin. Abbreviations: Dab, diaminobutyric acid; Thr, threonine; Phe, phenylalanine; Leu, leucine.
Figure 2
Figure 2
New polymyxin variants were developed primarily for three main purposes. The first is to reduce the risk of nephrotoxicity. The second is to improve PK/PD properties, thereby, increasing clinical efficacy in lower respiratory tract infections. The third is to ensure antimicrobial activity against pathogens resistant to old polymyxins. This figure presents the distribution of next-generation polymyxin derivatives that have reached and/or completed Phase I clinical trials and met these predetermined goals.
See this image and copyright information in PMC

References

    1. World Health Organization . Global Antimicrobial Resistance Surveillance System (GLASS) Report: Early Implementation 2017–2018. WHO; Geneva, Switzerland: 2019. [(accessed on 13 January 2022)]. Available online: https://www.who.int/publications/i/item/9789241515061.
    1. Centers for Disease Control and Prevention . Antibiotic Resistance Threats in the United States. CDC; Atlanta, GA, USA: 2019. [(accessed on 13 January 2022)]. Available online: https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-re....
    1. Murray C.J., Ikuta K.S., Sharara F., Swetschinski L., Aguilar G.R., Gray A., Han C., Bisignano C., Rao P., Wool E., et al. Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis. Lancet. 2022;399:629–655. doi: 10.1016/S0140-6736(21)02724-0. - DOI - PMC - PubMed
    1. Tacconelli E., Carrara E., Savoldi A., Harbarth S., Mendelson M., Monnet D.L., Pulcini C., Kahlmeter G., Kluytmans J., Carmeli Y., et al. Discovery, research, and development of new antibiotics: The WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 2018;18:318–327. doi: 10.1016/S1473-3099(17)30753-3. - DOI - PubMed
    1. Linden K.P., Kusne S., Coley K., Fontes P., Kramer D.J., Paterson D. Use of parenteral colistin for the treatment of serious infections due to antimicrobial-resistant Pseudomonas aeruginosa. Clin. Infect. Dis. 2003;37:e154–e160. doi: 10.1086/379611. - DOI - PubMed

LinkOut - more resources